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WO2024230752A1 - Dérivé de camptothécine, lieur, conjugué ligand-médicament et leur utilisation médicale - Google Patents

Dérivé de camptothécine, lieur, conjugué ligand-médicament et leur utilisation médicale Download PDF

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Publication number
WO2024230752A1
WO2024230752A1 PCT/CN2024/091808 CN2024091808W WO2024230752A1 WO 2024230752 A1 WO2024230752 A1 WO 2024230752A1 CN 2024091808 W CN2024091808 W CN 2024091808W WO 2024230752 A1 WO2024230752 A1 WO 2024230752A1
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ring
alkyl
membered
hydrogen
independently selected
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Chinese (zh)
Inventor
孙英杰
崔梦函
焦娇
王佳星
车黎明
张国富
陈文�
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Gan and Lee Pharmaceuticals Co Ltd
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Gan and Lee Pharmaceuticals Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the field of medical technology, and in particular to camptothecin derivatives, linkers, ligand-drug conjugates and their medical uses in treating or preventing proliferative diseases.
  • Camptothecin is a water-insoluble cytotoxic alkaloid produced from the tree Camptotheca accuminata grown in China and the tree Nothapodytes foetida grown in India. Camptothecin and its related analogs are known potential anticancer agents and have demonstrated therapeutic activity in vitro and in vivo.
  • Camptothecin and its analogs are known inhibitors of DNA topoisomerase I.
  • exitecan an analog of camptothecin, is also a DNA topoisomerase I inhibitor and exhibits strong anticancer activity.
  • Exotecan is a camptothecin derivative known to inhibit DNA topoisomerase I and exhibit anti-tumor effects. It was developed by Daiichi Sankyo Co., Ltd. and was initially used as a single chemotherapy drug and advanced to Phase III clinical trials. Its main indications are bone cancer, prostate cancer, breast cancer, pancreatic cancer, etc. Unlike irinotecan currently used in clinical practice, Exotecan does not require activation by the use of enzymes.
  • Exotecan compared with SN-38, which is the pharmacological entity of irinotecan, and topotecan, which is also used in clinical practice, Exotecan has stronger inhibitory activity against topoisomerase I and has stronger cytotoxic activity against a variety of cancer cells in vitro. Exotecan has not yet been successfully marketed as a single chemotherapy drug, which is speculated to be related to its higher cell activity, resulting in a narrow therapeutic window.
  • ligand-drug conjugate As a new type of targeted drug, ligand-drug conjugate (ADC) is generally composed of three parts: antibody or antibody-like ligand, small molecule drug and connecting part that couples ligand and drug.
  • Antibody-drug conjugate uses the antibody's specific recognition of antigen to transport drug molecules to the vicinity of target cells and effectively release drug molecules to achieve the purpose of treatment.
  • the ADC drug Mylotarg from Pfizer was first launched on the market, and the ADC field full of potential and challenges has since entered the public eye.
  • the pharmaceutical market has ushered in a new round of ADC research and development boom, and currently there are 13 ADC drugs on the market worldwide.
  • the antibody-drug conjugate DS-8201a (trade name: Enhertu) jointly developed and commercialized by Daiichi Sankyo and AstraZeneca was launched in December 2019.
  • the drug forms an amide derivative of exotecan and glycolic acid and connects them to form an ADC.
  • Enhertu has shown the potential to become a blockbuster.
  • the first aspect of the present invention provides a compound, such as a compound shown in Formula 1 or a pharmaceutically acceptable salt thereof,
  • R 16 , R 17 , R 19 are each independently selected from hydrogen, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, and C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl optionally substituted by R; preferably, R 16 , R 17 , R 19 are each independently selected from hydrogen and C 1-6 alkyl optionally substituted by R; more preferably, R 16 , R 17 , R 19 are each independently selected from hydrogen and C 1-6 al
  • R 20 is selected from N, and CR 20a ;
  • R 20a is selected from hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -C(O)CH 2 OH, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, and C 1-6 alkyl; preferably, R 20a is hydrogen or C 1-6 alkyl;
  • R 11 is selected from O and S;
  • Q is selected from 0, 1, 2, 3, and 4;
  • R 18 is selected from H, and -BR 3 ;
  • R 14 and R 15 are each independently selected from a hydrogen atom, a halogen, a C 1-8 alkyl group, and a C 1-8 haloalkyl group; preferably, R 14 and R 15 are each independently selected from a hydrogen atom, F, Cl, Br, I, a C 1-3 alkyl group, and a C 1-3 haloalkyl group; preferably, R 14 and R 15 are each independently -CH 3 or F; preferably, R 14 is -CH 3 , and/or R 15 is -F;
  • B is selected from -C(O)- and -P(O)(OH)-; preferably B is -C(O)-;
  • R 3 is selected from -(CH 2 CH 2 O) a C 1-6 alkyl, wherein when -(C(R 3a )(R 3b )) m - comprises a methylene unit, the n methylene units of said -(C(R 3a )(R 3b )) m - are each independently replaced by -N(R 5 )C(O)-, -C(O)-, -OC(O)-, -NR 5 -, -O-, -S-, -SO-, -SO 2 -, -P(R 5 )-, -P( ⁇ O)(R 5 )-, -N(R 5 )SO 2 -, -C( ⁇ S)-, -C( ⁇ NR 5 )-, -N ⁇ N- or -N ⁇ CH-;
  • a is an integer greater than or equal to 1, preferably, a is an integer from 1 to 20, and further preferably, a is selected from 1, 2, 3, 4, 5, 6, 7, and 8;
  • Ring W 1 , Ring W 2 , Ring W 3 , Ring W 4 , and Ring W 5 are each independently selected from 6-10 membered aryl or arylene, 5-10 membered heteroaryl or heteroarylene, 3-10 membered cycloalkyl or cycloalkylene, and 3-10 membered heterocyclyl or heterocyclylene, preferably, the heteroaryl, heteroarylene, heterocyclylene and heterocyclyl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S; and when R 3 is When W1 and W2 are fused together, when R3 is
  • W1 and W2 are fused together, W2 and W3 are fused together, and W3 and W4 are fused together;
  • Ring W1 , Ring W2 , Ring W3 , Ring W4 , and Ring W5 are each independently selected from 3-10 membered cycloalkyl, cycloalkylene, heterocyclylene, and heterocyclyl
  • the 3-10 membered cycloalkyl, cycloalkylene, heterocyclylene, and heterocyclyl are optionally substituted by one or more Rw1 , Rw2 , Rw3 , Rw4 , or Rw5
  • Ring W1 , Ring W2 , Ring W3 , Ring W4 , and Ring W5 are each independently selected from 6-10 membered aryl, 6-10 membered arylene, 5-10 membered heteroarylene, and 5-10 membered heteroaryl
  • the aryl, arylene, heteroarylene, and heteroaryl are optionally substituted by one or more Rw1 , Rw2 , Rw3 , Rw4 , or Rw5
  • each occurrence of Rw1 , Rw2 , Rw3 , Rw4 , and Rw5 is independently selected from hydrogen, protium, deuterium, tritium, halogen, -NO2 , -CN, -OR, -SR, -N( Ra )( Rb ), -C(O)R, -CO2R , -C(O)C(O)R, -C(O) CH2C (O)R, -S(O)R, -S(O)
  • R 13 is selected from the group consisting of a hydrogen atom, a halogen, a C 1-8 alkyl group, and a C 1-8 haloalkyl group; preferably, R 13 is a hydrogen atom;
  • R 12 is selected from the group consisting of a C 1-8 alkylene group N(R a )(R b ), a C 1-8 haloalkylene group N(R a )(R b ), a halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O
  • R 3a , R 3b , and R 5 are each independently, at each occurrence, hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or C 1-6 alkyl optionally substituted by R; and
  • n are each independently an integer greater than or equal to 1, and m ⁇ n; preferably, m and n are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and m ⁇ n; preferably, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -n is 0, 1, 2, 3, 4, or 5, and m ⁇ n;
  • R 12 , R 13 , and R 14 are each independently selected from hydrogen, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, and C 1-6 alkyl optionally substituted by R; preferably, R 12 , R 13 , and R 14 are each independently selected from hydrogen, F, Cl, Br, I, C 1-3 alkyl, -NO 2 , -CN, -OC 1-3 alkyl; or R R 12 and R 14 are each independently selected from hydrogen, F, Cl, Br
  • R 15 is C 1-8 alkylenehydroxy, C 1-8 alkyleneamino, -C(R a )(R b )-N(R a )-R 4c , -C(R a )(R b )-N(R a )-C(O)-R 4c , or -C(R a )(R b )-N(R a )-C(O)OR 4c ; preferably, R 15 is -CH 2 -NH 2 , -CH 2 -NH-C(O)-R 4c , -CH 2 -NH-C(O)OR 4c , or C 4 H 8 OH; preferably, R 15 is -CH 2 -NH 2 , or -(CH 2 ) 4 -OH; and
  • R, Ra , Rb , and R4c are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2 , -CN, -OH, -SH, -NH2 , -C(O)H, -CO2H , -C(O)C(O)H, -C(O) CH2C (O)H, -C(O) CH2OH , -S(O)H, -S(O ) 2H , -C(O) NH2 , -SO2NH2 , -OC(O)H, -N(H) SO2H , C1-6alkyl or C1-6alkylenehydroxy ; preferably, R, Ra , Rb , and R4c are each independently hydrogen, F, Cl, Br, I, CH2OH , or C2H4OH ;
  • R 11 is S, and R 18 is H, R 12 is selected from hydrogen, and -CH 2 N(R 3A )(R 4A );
  • R 14 and R 15 are each independently selected from hydrogen, halogen, -NO 2 , -CN, -OR', -N(R a1 )(R b1 ), -C(O)R', -CO 2 R', -C(O)C(O)R', -C(O)CH 2 C(O)R', -C(O)N(R a1 )(R b1 ), -SO 2 N(R a1 )(R b1 ), -OC(O)R', -N(R')SO 2 R', and C 1-6 alkyl; preferably, R 14 and R 15 are each independently selected from halogen, amino, -OR' and C 1-6 alkyl; further preferably, R 14 and R 15 are each independently selected from fluorine, chlorine, amino, -OC 1-6 alkyl and C 1-6 alkyl;
  • R 14 and R 15 can together form a saturated or unsaturated 4-10 membered cycloalkyl or a 5-membered or 6-membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is unsubstituted or substituted by one or more independently selected from halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or a C 1-6 alkyl, C 2-6 alkeny
  • R 13 is hydrogen, -C 1-6 alkyl or -C 1-6 alkylene-hydroxy; preferably, R 5A is hydrogen, C 1-6 alkyl or -(CH 2 ) 4 -hydroxy;
  • R3A and R4A are each independently selected at each occurrence from hydrogen, halogen, -OR', -N(R a1 )(R b1 ), -C(O)R', -C(S)R', -C(S)C(R a1 )(R b1 )OH, -C(O)CH 2 N(R a1 )(R b1 ), -CO 2 R', -C(O)C(O)R', -C(O)CH 2 C(O)R', -C(O)C(R a1 )(R b1 )OH, -C(O)-C 3-6 cycloalkylene-OH, -C(O)-C 1-6 alkylene-OH, -C 1-6 alkylene-OH-C(O)-C 3-6 cycloalkylene-C 1-6 alkylene-OH, -C(O)OC 1-6 alkylene-OH, -S
  • R', Ra1 , and Rb1 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2 , -CN, -OH, -SH, -NH2 , -C(O)H, -CO2H , -C(O)C(O)H, -C(O) CH2C (O)H, -S(O)H, -S(O) 2H , -C(O) NH2 , -SO2NH2 , -OC (O)H, -N(H) SO2H , C1-6alkyl , C2-6alkenyl or C2-6alkynyl, 3-, 4-, 5-, 6-, 7- or 8 - membered cycloalkyl, containing 1, 2, or 3 independently selected from N, O, and S is a 3-8 membered heterocyclyl, a 6-10 membered aryl, or a 5-10 membered heteroaryl containing
  • R 14 is -CH 3
  • R 15 is fluorine
  • R 13 is hydrogen
  • R 12 is and
  • R 14 is -O-CH 3
  • R 15 is fluorine
  • R 13 is hydrogen
  • R 12 is not and
  • R 12 is -CH 2 NH 2 , -CH 2 NHC 2 H 4 OH, -CH 2 N(CH 3 )C 2 H 4 OH, -CH 2 NHC 3 H 6 OH, and
  • R 14 when R 14 is fluorine, R 15 is fluorine, and R 13 is hydrogen, R 12 is not hydrogen;
  • R 14 is -CH 3
  • R 15 is chlorine
  • R 13 is hydrogen
  • R 12 is selected from and
  • R 12 is selected from -CH 2 NHC 2 H 4 OH, -CH 2 N(CH 3 )C 2 H 4 OH, -CH 2 NHC 3 H 6 OH, or
  • R 13 is selected from -(CH 2 ) 4 -OH
  • R 12 is hydrogen
  • R 14 and R 15 are fluorine
  • R 14 and R 15 form a 5-membered or 6-membered heterocyclic ring containing two oxygen atoms.
  • the structure of Formula 1 is selected from the following structures:
  • R 1 and R 2 are each independently selected from a hydrogen atom, a halogen, a C 1-8 alkyl group, and a C 1-8 haloalkyl group; preferably, R 1 and R 2 are each independently selected from a hydrogen atom, F, Cl, Br, I, a C 1-3 alkyl group, and a C 1-3 haloalkyl group; preferably, R 1 and R 2 are each independently -CH 3 or F; preferably, R 1 is -CH 3 , and/or R 2 is F;
  • A is selected from oxygen atoms and sulfur atoms
  • B is selected from -C(O)- and -P(O)(OH)-; preferably B is -C(O)-;
  • R 3 is selected from -(CH 2 CH 2 O) a C 1-6 alkyl, wherein when -(C(R 3a )(R 3b )) m - comprises a methylene unit, the n methylene units of said -(C(R 3a )(R 3b )) m - are each independently replaced by -N(R 5 )C(O)-, -C(O)-, -OC(O)-, -NR 5 -, -O-, -S-, -SO-, -SO 2 -, -P(R 5 )-, -P( ⁇ O)(R 5 )-, -N(R 5 )SO 2 -, -C( ⁇ S)-, -C( ⁇ NR 5 )-, -N ⁇ N- or -N ⁇ CH-;
  • a is an integer greater than or equal to 1, preferably, a is an integer from 1 to 20, and further preferably, a is selected from 1, 2, 3, 4, 5, 6, 7, and 8;
  • Ring W 1 , Ring W 2 , Ring W 3 , Ring W 4 , and Ring W 5 are each independently selected from 6 to 10 3-10 membered aryl or arylene, 5-10 membered heteroaryl or heteroarylene, 3-10 membered cycloalkyl or cycloalkylene, and 3-10 membered heterocyclyl or heterocyclylene, preferably, the heteroaryl, heteroarylene, heterocyclylene and heterocyclyl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S; and when R 3 is When W1 and W2 are fused together, when R3 is
  • W1 and W2 are fused together, W2 and W3 are fused together, and W3 and W4 are fused together;
  • Ring W1 , Ring W2 , Ring W3 , Ring W4 , and Ring W5 are each independently selected from 3-10 membered cycloalkyl, cycloalkylene, heterocyclylene, and heterocyclyl
  • the 3-10 membered cycloalkyl, cycloalkylene, heterocyclylene, and heterocyclyl are optionally substituted by one or more Rw1 , Rw2 , Rw3 , Rw4 , or Rw5
  • Ring W1 , Ring W2 , Ring W3 , Ring W4 , and Ring W5 are each independently selected from 6-10 membered aryl, 6-10 membered arylene, 5-10 membered heteroarylene, and 5-10 membered heteroaryl
  • the aryl, arylene, heteroarylene, and heteroaryl are optionally substituted by one or more Rw1 , Rw2 , Rw3 , Rw4 , or Rw5
  • each occurrence of Rw1 , Rw2 , Rw3 , Rw4 , and Rw5 is independently selected from hydrogen, protium, deuterium, tritium, halogen, -NO2 , -CN, -OR, -SR, -N( Ra )( Rb ), -C(O)R, -CO2R , -C(O)C(O)R, -C(O) CH2C (O)R, -S(O)R, -S(O)
  • R6 is selected from the group consisting of a hydrogen atom, a halogen, a C1-8 alkyl group, and a C1-8 haloalkyl group; preferably, R6 is a hydrogen atom; R7 is selected from the group consisting of a C1-8 alkylene N(R a )(R b ), a C1-8 haloalkylene N(R a )(R b ), a halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R,
  • R7 is selected from -CH2N ( Ra )( Rb ); or, R6 and R7 together with the carbon atom to which they are attached form a saturated or unsaturated 5-10 membered cycloalkyl or a 5-10 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O , P and S , wherein the cycloalkyl or heterocyclyl is optionally substituted by one or more independently selected from halogen, -NO2 , -CN, -OR, -SR, -N(Ra ) ( Rb ), -C(O)R, -CO2R , -C(O)C(O)R, -C(O) CH2C (O)R, -S(O)R, -S(O) 2R , -C(O)N( Ra )( Rb ), -SO2N ( Ra )( Rb ) ⁇ -OC(O)R ⁇ -N(
  • R 3a , R 3b , and R 5 are each independently, at each occurrence, hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or C 1-6 alkyl optionally substituted by R;
  • R, Ra , and Rb are each independently, at each occurrence, hydrogen, protium, deuterium, tritium, halogen , -NO2, -CN, -OH, -SH, -NH2 , -C(O)H, -CO2H , -C(O)C(O)H, -C(O) CH2C (O)H, -C(O) CH2OH , -S(O)H, -S(O) 2H , -C(O) NH2 , -SO2NH2 , -OC(O)H, -N(H) SO2H , C1-6 alkylenehydroxy, or C1-6 alkyl; and
  • n are each independently an integer greater than or equal to 1, and m ⁇ n; preferably, m and n are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and m ⁇ n; preferably, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -n is 0, 1, 2, 3, 4, or 5, and m ⁇ n;
  • R 1c , R 2c , and R 5c are each independently selected from hydrogen, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, and C 1-6 alkyl optionally substituted by R; preferably, R 1c , R 2c , and R 5c are each independently selected from hydrogen, F, Cl, Br, I, C 1-3 alkyl, -NO 2 , -CN, -OC 1-3 alkyl; or R 1c and R R 1c and the carbon
  • R 6c is C 1-8 alkylenehydroxy, C 1-8 alkyleneamino, -C(R a )(R b )-N(R a )-R 4c , -C(R a )(R b )-N(R a )-C(O)-R 4c , or -C(R a )(R b )-N(R a )-C(O)OR 4c ; preferably, R 6c is -CH 2 -NH 2 , -CH 2 -NH-C(O)-R 4c , -CH 2 -NH-C(O)OR 4c , or C 4 H 8 OH; preferably, R 6c is -CH 2 -NH 2 , or -(CH 2 ) 4 -OH; and
  • R, Ra , Rb , and R4c are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2 , -CN, -OH, -SH, -NH2 , -C(O)H, -CO2H , -C(O)C(O)H, -C(O) CH2C (O)H, -C(O) CH2OH , -S(O)H, -S(O ) 2H , -C(O) NH2 , -SO2NH2 , -OC(O)H, -N(H) SO2H , C1-6alkyl or C1-6alkylenehydroxy ; preferably, R, Ra , Rb , and R4c are each independently hydrogen, F, Cl, Br, I, CH2OH , or C2H4OH ;
  • R 6A is selected from hydrogen, and -CH 2 N(R 3A )(R 4A );
  • R 1A , and R 2A are each independently selected from hydrogen, halogen, -NO 2 , -CN, -OR', -N(R a1 )(R b1 ), -C(O)R', -CO 2 R', -C(O)C(O)R', -C(O)CH 2 C(O)R', -C(O)N(R a1 )(R b1 ), -SO 2 N(R a1 )(R b1 ), -OC(O)R', -N(R')SO 2 R', and C 1-6 alkyl; preferably, R 1A and R 2A are each independently selected from halogen, amino, -OR' and C 1-6 alkyl; further preferably, R 1A and R 2A are each independently selected from fluorine, chlorine, amino, -OC 1-6 alkyl and C 1-6 alkyl;
  • R 1A and R 2A can together form a saturated or unsaturated 4-10 membered cycloalkyl or a 6-membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is unsubstituted or substituted by one or more independently selected from halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or a C1-6 alkyl, C1-6 alkenyl or C1-6 al
  • R 5A is hydrogen or C 1-6 alkyl
  • R3A and R4A at each occurrence are each independently selected from hydrogen, halogen, -OR', -N(R a1 )(R b1 ), -C(O)R', -C(S)R', -C(S)C(R a1 )(R b1 )OH, -C(O)CH 2 N(R a1 )(R b1 ), -CO 2 R', -C(O)C(O)R', -C(O)CH 2 C(O)R', -C(O)C(R a1 )(R b1 )OH, -C(O)-C 3-6 cycloalkylene-OH, -C(O)-C 1-6 alkylene-OH, -C(O)-C 3-6 cycloalkylene-C 1-6 alkylene-OH, -C(O)OC 1-6 alkylene-OH, -S(O)R', -S
  • R', Ra1 , and Rb1 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2 , -CN, -OH, -SH, -NH2 , -C(O)H, -CO2H , -C(O)C(O)H, -C(O) CH2C (O)H, -S(O)H, -S(O) 2H , -C(O) NH2 , -SO2NH2 , -OC(O)H, -N(H) SO2H , C1-6 alkyl, C2-6 alkenyl, or C or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, 3, 4, 5, 6, 7 or 8 membered cycloalkyl, 3-8 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 6-10
  • R 1A is -CH 3
  • R 2A is fluorine
  • R 5A is hydrogen
  • R 6A is and
  • R 1A is -O-CH 3
  • R 2A is fluorine
  • R 5A is hydrogen
  • R 6A is not and
  • R 1A and R 2A form a 1,4-dioxo six-membered ring and R 5A is hydrogen
  • R 6A is -CH 2 NH 2 , -CH 2 NHC 2 H 4 OH, -CH 2 N(CH 3 )C 2 H 4 OH, -CH 2 NHC 3 H 6 OH
  • R 1A and R 2A form a 1,4-dioxo six-membered ring and R 5A is hydrogen
  • R 6A is -CH 2 NH 2 , -CH 2 NHC 2 H 4 OH, -CH 2 N(CH 3 )C 2 H 4 OH, -CH 2 NHC 3 H 6 OH, and
  • R 1A is fluorine
  • R 2A is fluorine
  • R 5A is hydrogen
  • R 6A is not hydrogen
  • R 1A is -CH 3
  • R 2A is chlorine
  • R 5A is hydrogen
  • R 6A is selected from and
  • R 6A is selected from -CH 2 NHC 2 H 4 OH, -CH 2 N(CH 3 )C 2 H 4 OH, -CH 2 NHC 3 H 6 OH, or
  • R 5A is selected from -C 4 H 8 OH
  • R 6A is hydrogen
  • R 1A and R 2A are fluorine
  • R 1A and R 2A form a 5-membered or 6-membered heterocyclic ring containing two oxygen atoms.
  • each occurrence of Ring W1 , Ring W2 , Ring W3 , Ring W4 , and Ring W5 is independently selected from 6- or 8-membered aryl or arylene, 5-, 6-, 7-, or 8-membered heteroaryl or heteroarylene containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, 4-, 5-, 6-, 7-, or 8-membered cycloalkyl or cycloalkylene, and 4-, 5-, 6-, 7-, or 8-membered heterocyclyl or heterocyclylene containing 1, 2, 3 , or 4 heteroatoms independently selected from N, O, and S.
  • Ring W1 , Ring W2 , Ring W3, Ring W4 , and Ring W5 are each independently selected from 4-8 membered cycloalkyl, cycloalkylene, heterocyclylene, and heterocyclyl
  • R 3A at each occurrence is independently selected from hydrogen, -C(O)R', -C(S)R', -C(S)C(R a1 )(R b1 )OH, -C(O)CH 2 N(R a1 )(R b1 ), -CO 2 R', -C(O)C(R a1 )(R b1 )OH, -C(O)-C 3-6 cycloalkylene-OH, -C(O)-C 1-6 alkylene-OH, -C(O)-C 3-6 cycloalkylene-C 1-6 alkylene-OH, -C(O)OC 1-6 alkylene-OH, and C 1-6 alkyl, C 1-6 alkenyl and C 1-6 alkynyl optionally substituted by R'; and/or
  • R 4A is selected from hydrogen, or C 1-6 alkyl; and/or
  • R', Ra1 , and Rb1 at each occurrence, are each independently hydrogen, fluorine, chlorine, -OH, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, 3-, 4-, 5- or 6-membered cycloalkyl, or 3-, 4-, 5- or 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S , wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-, 4-, 5- or 6-membered cycloalkyl, 3-, 4-, 5- or 6-membered heterocyclyl is unsubstituted or substituted with 1 or 2 substituents independently selected from fluorine, chlorine, -NO2 , -CN, -OH, -NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and hydroxyC1-6 alkylene.
  • the compound is selected from:
  • R 3 is selected from the following groups:
  • the compound is selected from:
  • the compound as shown in Formula 1A or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt thereof.
  • R1 and R2 are each independently selected from a hydrogen atom, a halogen group, a C1-8 alkyl group, a C1-8 haloalkyl group;
  • A is selected from an oxygen atom or a sulfur atom
  • B is selected from -C(O)- or -P(O)(OH)-;
  • R 3 is selected from -(C(R 3a )(R 3b )) m -R 3c , wherein when -(C(R 3a )(R 3b )) m - comprises a methylene unit, the n methylene units of said -(C(R 3a )(R 3b )) m - are each independently replaced by -N(R 5 )C(O)-, -C(O)N(R 5 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 5 -, -O-, -S-, -SO-, -SO 2 -, -P(R 5 )-, -P( ⁇ O)(R 5 )-, -N(R 5 )SO 2 -, -SO 2 N(R 5 )-, -C( ⁇ S)-, -C( ⁇ NR 5 )-, -N ⁇ N
  • Ring W 1 , ring W 2 , ring W 3 , ring W 4 , and ring W 5 are each independently selected from a 6-10 membered aryl group, a 5-10 membered heteroaryl group, a 3-10 membered cycloalkyl group, or a 3-10 membered heterocyclyl group;
  • Ring W1 , Ring W2 , Ring W3 , Ring W4 , and Ring W5 are each independently selected from cycloalkyl or heterocyclyl
  • the cycloalkyl or heterocyclyl is substituted by one or more Rw1 , Rw2 , Rw3 , Rw4 , and Rw5
  • Ring W1 , Ring W2 , Ring W3 , Ring W4 , and Ring W5 are each independently selected from aryl or heteroaryl
  • the aryl or heteroaryl is substituted by one or more Rw1 , Rw2 , or Rw3 , Rw4 , or Rw5
  • each occurrence of Rw1 , Rw2, Rw3 , Rw4 , or Rw5 is independently selected from hydrogen, protium, deuterium , tritium, halo, -NO2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b
  • R 6 is selected from hydrogen atom, halogen, C 1-8 alkyl, C 1-8 haloalkyl; preferably, R 6 is selected from hydrogen atom;
  • R is selected from C 1-8 alkylene N(R a )(R b ), C 1-8 haloalkylene N(R a )(R b ), halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or a C 1-6 aliphatic group optionally substituted by R; preferably, R is selected from C 1-8 alkylene N(R a )(R b ), or C 1-8 haloalkylene N(R a )
  • R6 and R7 can form, together with the carbon atom to which they are attached, a saturated or unsaturated 5-10 membered cycloalkyl or a 6-10 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O, and S, wherein the cycloalkyl or heterocyclic group is substituted by one or more independently selected from halogen, -NO2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R , -C(O)C(O)R, -C(O) CH2C (O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or a C 1-6 aliphatic group optionally substitute
  • R 3a , R 3b , R 3c , and R 5 are each independently, at each occurrence, hydrogen, protium, deuterium, tritium, halo, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or a C 1-6 aliphatic group optionally substituted by R;
  • R, Ra , and Rb are each independently, at each occurrence, hydrogen, protium, deuterium, tritium, halo , -NO2, -CN, -OH, -SH, -NH2 , -C(O)H, -CO2H , -C(O)C(O)H, -C(O) CH2C (O)H, -C(O) CH2OH , -S(O)H, -S(O) 2H , -C (O) NH2 , -SO2NH2 , -OC(O)H, -N(H) SO2H , or a C1-6 aliphatic group;
  • n and n are integers greater than or equal to 0;
  • R 3 is -(C(R 3a )(R 3b )) m -R 3c
  • Ring W2 is phenyl or oxolanyl, and ring W3 is phenyl or pyridyl;
  • Ring W 1 , Ring W 2 or Ring W 3 is selected from cycloalkyl or heterocyclyl
  • R3 is When -(C(R 3a )(R 3b )) m - comprises a methylene unit, the n methylene units of -(C(R 3a )(R 3b )) m - are each independently replaced by -N(R 5 )C(O)-, -C(O)N(R 5 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 5 -, -O-, -S-, -SO-, -SO 2 -, -P(R 5 )-, -P( ⁇ O)(R 5 )-, -N(R 5 )SO 2 -, -SO 2 N(R 5 )-, -C( ⁇ S)-, -C( ⁇ NR 5 )-, -N ⁇ N-, -CH ⁇ N-, or -N ⁇ CH-;
  • R3 is m1 is 1 An integer from 4 to 6, ring W1 is selected from 6-10 membered aryl, 4-8 membered cycloalkyl, 4-8 membered saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected from N, O, S, 5-8 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S,
  • Ring W1 is selected from 4-8 membered cycloalkyl or 4-8 membered heterocyclyl
  • Ring W1 is selected from 6-10 membered aryl or 5-8 membered heteroaryl
  • the phenyl or 5-8 membered heteroaryl is substituted by one or more Rw1 , each occurrence of which is independently selected from hydrogen, protium, deuterium, tritium, halo , -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R , -C(O)C(O)R, -C(O) CH2C (O)R, -S(O)R, -S(O) 2R , -C( O )N(R a )(R b ), -SO2N (R a )(R b ), -OC(O)R, -N(R) SO2R , or a C 1-6 aliphatic group optionally substituted by R;
  • ring W 1 is a 5-8 membered heteroaryl substituted by one or more R w1
  • the heteroaryl is pyridyl or pyrazolyl
  • ring W 1 is selected from a 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms, each occurrence of which is independently selected from N, O or S; preferably, ring W 1 is
  • R3 is When -(C(R 3a )(R 3b )) m - comprises a methylene unit, the n methylene units of said -(C(R 3a )(R 3b )) m - are each independently replaced by -N(R 5 )C(O)-, -C(O)N(R 5 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 5 -, -O-, -S-, -SO-, -SO 2 -, -P(R 5 )-, -P( ⁇ O)(R 5 )-, -N(R 5 )SO 2 -, -SO 2 N(R 5 )-, -C( ⁇ S)-, -C( ⁇ NR 5 )-, -N ⁇ N-, -CH ⁇ N- or -N ⁇ CH-; wherein ring W 1 and ring W 2 2 are each
  • Ring W2 is selected from the group consisting of
  • Ring W1 or Ring W2 is selected from cycloalkyl or heterocyclyl
  • Rw1 or Rw2 is substituted by one or more Rw1 or Rw2 , each occurrence of which is independently selected from hydrogen, protium, deuterium, tritium, halogen, -NO2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R , -C(O)C(O)R, -C(O) CH2C (O)R, -S(O)R, -S(O) 2R , -C(O)N(R a )(R b ), -SO2N (R a )(R b ), -OC(O)R, -N(R) SO2R , or a C 1-6 aliphatic group optionally substituted by R, R 4 is a single bond or
  • Ring W1 or Ring W2 is a 6-10 membered aryl or 5-8 membered heteroaryl
  • the aryl or heteroaryl is substituted by one or more Rw1 or Rw2 , each occurrence of which is independently selected from hydrogen, protium, deuterium, tritium, halo , -NO2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R , -C(O)C(O)R, -C(O) CH2C (O)R, -S(O)R, -S(O) 2R , -C(O)N(R a )(R b ), -SO2N (R a )(R b ), -OC(O)R, -N(R) SO2R , or a C1-6 aliphatic group optionally substituted by R;
  • R3 is When -(C(R 3a )(R 3b )) m - comprises a methylene unit, the n methylene units of -(C(R 3a )(R 3b )) m - are each independently replaced by -N(R 5 )C(O)-, -C(O)N(R 5 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 5 -, -O-, -S-, -SO-, -SO 2 -, -P(R 5 )-, -P( ⁇ O)(R 5 )-, -N(R 5 )SO 2 -, -SO 2 N(R 5 )-, -C( ⁇ S)-, -C( ⁇ NR 5 )-, -N ⁇ N-, -CH ⁇ N- or -N ⁇ CH-; rings W 1 , W 2 , W 3 and W 4 are
  • n is an integer from 1 to 20;
  • n is an integer from 0 to 8.
  • R 1c , R 2c , and R 5c are each independently selected from hydrogen, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or a C 1-6 aliphatic group optionally substituted by R;
  • R 1c and R 2c together with the carbon atom to which they are attached form a saturated or unsaturated 5-10 membered cycloalkyl or a 6-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is substituted by one or more independently selected from halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or a C 1-6 aliphatic group optionally substituted by
  • R 6c is C 1-8 alkylhydroxy, C 1-8 alkylamino, -C(R a )(R b )-N(R a )-R 4c , -C(R a )(R b )-N(R a )-C(O)-R 4c , or -C(R a )(R b )-N(R a )-C(O)OR 4c ;
  • R, Ra , Rb , and R4c are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2 , -CN, -OH, -SH, -NH2 , -C(O)H, -CO2H , -C(O)C(O)H, -C(O) CH2C (O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2 , -OC ( O)H, -N(H) SO2H , C1-6 aliphatic, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered the C 1-6 aliphatic group, 3-8 membered cycloalkyl group, 3-8 membered heterocyclyl group, 6-10 membered aryl group or 5-10 membered heteroaryl group is unsubstituted or substituted by one or more groups independently
  • the second aspect of the present invention provides a ligand-drug conjugate having a structure as shown in Formula 3 or a pharmaceutically acceptable salt thereof,
  • Ab is the ligand, L is the linker part, and D is the drug part;
  • n is any integer or decimal from 1 to 15; preferably, n is any integer or decimal from 1 to 13; preferably, n is any integer or decimal from 3 to 10;
  • the drug portion D is any of the following structures,
  • R 1 , R 2 , R 3 , R 6 , R 7 , A, B, R 1c , R 2c , R 5c , R 1A , R 2A , R 3A , R 4A , and q are as defined in any one of claims 2 , 3 , or 4 ;
  • R 6A is selected from hydrogen, -CH(CH 3 )N(R 3A )(R 4A ) and -CH 2 N(R 3A )(R 4A );
  • R 5A is hydrogen or C 1-6 alkyl
  • R 1s , R 2s , R 7s , and R 7ss are each independently C 1-8 alkylene NR-, C 1-8 haloalkylene NR-, -OR, -SR, -NR-, -C(O)NR-, -SO 2 NR-, or -O-CH 2 C(O)NR-; preferably, R 1s , R 2s , R 7s , and R 7ss are each independently -NR-, -NR-CH 2 -, or -O-CH 2 C(O)NR-; preferably, R 1s , R 2s , R 7s , and R 7ss are each independently -NH-, -NH-CH 2 -, or -O-CH 2 C(O)NH-;
  • R6bs is independently selected from -CH2N (R a1 )-, -CH2N (R a1 ) -C2-5 alkylene-O-, -CH2N (R a1 )C(O)C(R a1 )(R b1 )O-, -CH2N (R a1 )C(S)C(R a1 )(R b1 )O-, -CH2N (R a1 )C(O)-C3-8 cycloalkylene - O-, -CH2N (R a1 )C(O ) -C2-5 alkylene-O-, -CH2N(R a1 )C(O)C(R a1 )(R b1 )N(R a1 )-, -CH2N (R a1 )C(O) -C3-8 cycloalkylene-C(R a1 )(R
  • R, Ra1 , and Rb1 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2 , -CN, -OH, -SH, -NH2 , -C(O)H, -CO2H , -C(O)C(O)H, -C(O) CH2C (O)H, -S(O)H, -S(O) 2H , -C(O) NH2 , -SO2NH2 , -OC(O)H, -N(H) SO2H , C1-6 alkyl, C2-6 alkenyl, or C or 5-10 membered heteroaryl groups, wherein the C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, 3, 4, 5, 6, 7 or 8 membered cycloalkyl, 3-8 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 6-10
  • R 6aa is selected from -C 1-8 alkylene N(R a2 )-, -CH 2 N(R a2 )C(O)C(R a2 )(R b2 )O-, -CH 2 N(R a2 )C(O)-C 3-8 cycloalkylene-O-, -C 2-5 alkylene-O-, -CH 2 N(R a2 )C(O)OC 2-5 alkylene-O-; preferably R 6aa is -CH 2 -NH 2 , or -(CH 2 ) 4 -O-;
  • Ra2 and Rb2 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2 , -CN, -OH, -SH, -NH2 , -C(O)H, -CO2H , -C(O)C(O)H, -C(O) CH2C (O)H, -S(O) H , -S(O) 2H , -C(O) NH2, -SO2NH2 , -OC(O)H, -N(H) SO2H , or C1-6alkylenehydroxy ; preferably, Ra2 and Rb2 are each independently hydrogen, F, Cl, Br, I, -CH2OH , or -C2H4OH .
  • the drug moiety D is selected from any of the following structures,
  • the linking moiety L is L 1 -L 2 -L 3 -L 4 ;
  • W is selected from C 1-10 alkylene, C 1-10 alkylene-cycloalkylene, C 1-10 heteroalkylene, C 1-10 alkylene-cycloheteroalkylene, or C 1-10 heteroalkylene-cycloalkylene, preferably W is C 1-8 alkylene, C 1-8 alkylene-cycloalkylene or C 1-8 heteroalkylene, the heteroalkylene containing 1 to 3 heteroatoms independently selected from N, O or S, wherein the alkylene, cycloalkylene and heteroalkylene are unsubstituted or each independently optionally further substituted by one or more substituents selected from halogen, hydroxyl, -CN, amino, alkyl, haloalkyl, deuterated alkyl, alkoxy and cycloalkyl, preferably, the alkylene, cycloalkylene and heteroalkylene are unsubstituted or each independently optionally further substituted by one or more substituents selected from halogen, hydroxyl,
  • X is selected from a single bond, a C 1-10 alkylene group, a C 1-10 alkylene-cycloalkylene group, a C 1-10 heteroalkylene group, a C 1-10 alkylene-cycloheteroalkylene group, or a C 1-10 heteroalkylene-cycloalkylene group, preferably X is selected from a single bond, a C 1-8 alkylene group, a C 1-8 alkylene-cycloalkylene group, or a C 1-8 heteroalkylene group;
  • Ar 1 is selected from 6-10 membered aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-10 membered cycloalkyl or 3-10 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O, P and S; preferably, Ar 1 is selected from
  • L3 is a peptide residue consisting of 2 to 7 amino acids, preferably L3 is a peptide residue consisting of 2, 3, 4, 5 or 6 amino acids, wherein the amino acids are unsubstituted or optionally further substituted with one or more substituents selected from halogen, hydroxyl, -CN, amino, alkyl, haloalkyl, deuterated alkyl, alkoxy and cycloalkyl, preferably, optionally further substituted with one or more substituents selected from halogen, hydroxyl, -CN, amino, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy and C5-8 cycloalkyl;
  • R 1L and R 2L are the same or different and are each independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a deuterated C 1-6 alkyl group and a -C 1-6 alkylene group-OH;
  • R 3L and R 4L are the same or different and are each independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a deuterated C 1-6 alkyl group and a -C 1-6 alkylene group-OH; and
  • the L1 end is connected to the ligand, and the L4 end is connected to the drug moiety.
  • L3 is a peptide residue consisting of 2-6 amino acids selected from glycine, phenylalanine, alanine, valine, lysine, citrulline, serine, glutamic acid, and aspartic acid; preferably, it is a dipeptide residue, a tripeptide residue, or a tetrapeptide residue selected from alanine, phenylalanine, glycine, lysine, and citrulline; preferably, L3 is a peptide residue selected from the following: glycine-phenylalanine-glycine, alanine-alanine-alanine-glycine, alanine-alanine-alanine, glycine-glycine-phenylalanine-glycine, valine-citrulline, and valine-alanine;
  • the peptide residue is unsubstituted or optionally further substituted by one or more substituents selected from halogen, hydroxyl, -CN, amino, alkyl, haloalkyl, deuterated alkyl, alkoxy and cycloalkyl, preferably, optionally further substituted by halogen, hydroxyl, -CN, amino, and C 1-6 alkyl substituents.
  • linking moiety L is selected from:
  • the ligand-drug conjugate is selected from the following structures:
  • n is an integer or decimal from 1 to 10; preferably, n is an integer or decimal from 3 to 8; and Ab is a ligand.
  • the Ab is an antibody or an antigen-binding fragment thereof or a polypeptide, wherein the antibody is selected from a chimeric antibody, a humanized antibody, and a fully human antibody;
  • the antibody or antigen-binding fragment thereof is selected from anti-TROP-2 antibody, anti-HER2 (ErbB2) antibody, anti-NECTIN4 antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-LIV-1 antibody, anti-ROR1 antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-MUCl antibody, anti-Lewis Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody, anti-TROP
  • the antibody or antigen-binding fragment thereof is an anti-TROP-2 antibody, an anti-NECTIN4 antibody, an anti-B7-H3 antibody, an anti-HER2 (ErbB2) antibody, an anti-HER3 (ErbB3) antibody, an anti-LIV-1 antibody, an anti-ROR1 antibody or an antigen-binding fragment thereof;
  • the antibody or antigen-binding fragment thereof is an anti-HER2 (ErbB2) antibody, an anti-NECTIN4 antibody, an anti-B7-H3 antibody or an antigen-binding fragment thereof;
  • the antibody or antigen-binding fragment thereof is trastuzumab, ifinatamab monoclonal antibody or PADCEV monoclonal antibody.
  • the third aspect of the present invention provides a compound, such as a compound shown in Formula 5 or a pharmaceutically acceptable salt thereof,
  • L j is selected from and W, X are as defined in any one of the second aspect of the present invention.
  • the compound is selected from:
  • the fourth aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound or ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of the first aspect, the second aspect or the third aspect, and a pharmaceutically acceptable carrier.
  • the fifth aspect of the present invention provides a pharmaceutical composition, the compound or ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of the first aspect, the second aspect or the third aspect of the present invention, or the fourth aspect of the present invention Use of the pharmaceutical composition described above in the preparation of a drug for treating or preventing tumors;
  • the tumor is a cancer associated with B7-H3 expression, HER2 expression, or NECTIN4 expression;
  • the cancer is selected from breast cancer, gastric cancer, melanoma and lung cancer.
  • the sixth aspect of the present invention provides a method for preventing or treating tumors, comprising administering an effective amount of the compound or ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of the first, second or third aspects of the present invention, or the pharmaceutical composition according to the fourth aspect to a subject in need thereof;
  • the tumor is a cancer associated with B7-H3 expression, HER2 expression, or NECTIN4 expression;
  • the cancer is selected from breast cancer, gastric cancer, melanoma and lung cancer.
  • the sixth aspect of the present invention provides a compound or ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of the first aspect, the second aspect or the third aspect, or the pharmaceutical composition according to the fourth aspect, for use in preventing or treating tumors;
  • the tumor is a cancer associated with B7-H3 expression, HER2 expression or NECTIN4 expression; preferably, the cancer is selected from breast cancer, gastric cancer, melanoma and lung cancer.
  • the sixth aspect of the present invention provides a use of the compound described in the first aspect of the present invention, characterized in that it is used as a toxin in an antibody-drug conjugate to prepare an antibody-drug conjugate.
  • FIG1 shows the inhibitory activity of B7H3-ADC-27 in the B7H3-negative Raji cell line in Experimental Example 6;
  • FIG2 shows the inhibitory activity of B7H3-ADC-27 in the mixed B7H3-positive A375 and negative Raji cell lines in Experimental Example 6;
  • FIG3 shows the inhibitory activity of B7H3-ADC-1 in the B7H3-negative Raji cell line in Experimental Example 6;
  • FIG4 shows the inhibitory activity of B7H3-ADC-1 in the mixed B7H3-positive A375 and negative Raji cell lines in Experimental Example 6;
  • FIG5 shows the tumor inhibition activity of the ADC molecule in Experimental Example 6 in an animal model in which both B7H3 negative cells and positive cells exist;
  • FIG6 is a tumor growth curve of mice in Experimental Example 7.
  • FIG7 is a curve showing the weight change of mice in Experimental Example 7.
  • FIG8 is a tumor growth curve of mice in Experimental Example 8.
  • FIG9 is a curve showing the weight change of mice in Experimental Example 8.
  • FIG10 is a curve showing the weight change of mice in Experimental Example 9;
  • FIG11 is a tumor growth curve of mice in Experimental Example 10.
  • FIG. 12 shows the tumor tissue of mice in Experimental Example 10.
  • compositions of the present invention may exist in free form, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, prodrugs, stereoisomers (including but not limited to diastereomers and enantiomers), tautomers, solvates, polymorphs and isotopic compounds, which can directly or indirectly provide the compounds of the present invention or their metabolites after being administered to patients in need thereof. Therefore, when referring to "compounds of the present invention” herein, it is also intended to cover the above-mentioned various derivative forms of the compounds.
  • pharmaceutically acceptable salt refers to a salt that retains the biological effectiveness of the free acid and base of a particular compound without any adverse biological effects.
  • pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, such as salts formed with inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, etc.; or salts formed with organic acids such as malic acid, fumaric acid, maleic acid, benzoic acid, phenylacetic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, glycolic acid, cinnamic acid, pyruvic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, acrylic acid, mandelic acid, etc.; or (2) base addition salts, such as salts formed with alkali metals such as lithium, sodium, potassium, etc.; salts formed with
  • Prodrugs of the compounds of the present invention are included in the protection scope of the present invention.
  • the prodrug refers to a functional derivative that is easily converted into the desired compound in vivo. Therefore, the term "administration" in the treatment method provided by the present invention includes the administration of the compounds disclosed in the present invention, or although not explicitly disclosed, it can be converted into the compounds disclosed in the present invention in vivo after administration to the subject to treat the various diseases described. Conventional methods for selecting and preparing suitable prodrug derivatives have been recorded in books such as "Design of Prodrugs" (H. Bundgaard, Elsevier, 1985).
  • the compounds of the present invention may contain one or more asymmetric centers and may thus produce diastereomers and optical isomers.
  • the present invention includes all possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers and pharmaceutically acceptable salts thereof.
  • the compounds of the present invention do not have a precise definition of the stereostructure of a certain position of the compounds.
  • the present invention includes all stereoisomers of the compounds and pharmaceutically acceptable salts thereof. Moreover, mixtures of stereoisomers and isolated specific stereoisomers are also included in the present invention. In the synthetic process of preparing such compounds, or using During the racemization or epimerization process known to those skilled in the art, the product obtained may be a mixture of stereoisomers.
  • the present invention includes any possible tautomerism and pharmaceutically acceptable salts thereof, and mixtures thereof.
  • the present invention includes any possible solvates and polymorphs.
  • the type of solvent forming the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable.
  • similar solvents such as water, ethanol, propanol, acetone, etc. can be used.
  • the present invention also includes all pharmaceutically acceptable isotopic compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (2H), tritium (3H)); isotopes of carbon (e.g., 13C and 14C); isotopes of chlorine (e.g., 37Cl); isotopes of iodine (e.g., 125I); isotopes of nitrogen (e.g., 13N and 15N); isotopes of oxygen (e.g., 17O and 18O); isotopes of phosphorus (e.g., 32P); and isotopes of sulfur (e.g., 34S).
  • isotopes of hydrogen e.g., deuterium (2H), tritium (3H)
  • isotopes of carbon e.g., 13C and 14C
  • isotopes of chlorine e.g., 37Cl
  • ligand refers to a macromolecular compound that can recognize and bind to an antigen or receptor associated with a target cell.
  • the function of the ligand is to present the drug to the target cell population bound to the ligand.
  • the ligand is represented by Ab, and the ligand can form a connection bond with the linker through a heteroatom on the ligand, preferably an antibody or an antigen-binding fragment thereof or a polypeptide, and the antibody is selected from a chimeric antibody, a humanized antibody, a fully human antibody or a mouse antibody; preferably a monoclonal antibody.
  • ligand binding component refers to a group capable of attaching to a ligand moiety.
  • drug linking component refers to a group capable of linking to a drug moiety.
  • drug refers to a cytotoxic drug, represented by D, which is a chemical molecule that has a strong ability to disrupt the normal growth of tumor cells.
  • linker unit or “linking fragment” or “linking unit” or “linking part” or “linker” refers to a chemical structure fragment or bond that is connected to a ligand at one end and to a drug at the other end, and can also be connected to other linkers before being connected to the drug.
  • ligand-drug conjugate refers to a ligand connected to a biologically active drug via a stable linker.
  • the "ligand-drug conjugate” is preferably an antibody-drug conjugate (ADC), which refers to a monoclonal antibody or antibody fragment connected to a biologically active toxic drug via a stable linker.
  • ADC antibody-drug conjugate
  • antibody refers to immunoglobulin, which is a tetrapeptide chain structure composed of two identical heavy chains and two identical light chains connected by interchain disulfide bonds.
  • the amino acid composition and arrangement order of the constant region of the immunoglobulin heavy chain are different, so their antigenicity is also different.
  • immunoglobulins can be divided into five categories, or called immunoglobulin isotypes, namely IgM, IgD, IgG, IgA and IgE, and their corresponding heavy chains are ⁇ chain, ⁇ chain, ⁇ chain, ⁇ chain, and ⁇ chain respectively.
  • immunoglobulin isotypes namely IgM, IgD, IgG, IgA and IgE, and their corresponding heavy chains are ⁇ chain, ⁇ chain, ⁇ chain, ⁇ chain, and ⁇ chain respectively.
  • the same type of Ig is based on its hinge region amino acid composition and the number and position of heavy chain disulfide bonds.
  • IgG can be divided into IgG1, IgG2, IgG3, and IgG4.
  • Light chains are divided into ⁇ chains or ⁇ chains according to the difference in the constant region.
  • Each of the five types of Ig can have ⁇ chains or ⁇ chains.
  • the antibodies disclosed herein are preferably specific antibodies against cell surface antigens on target cells, and non-limiting examples thereof are the following antibodies: anti-TROP-2 antibody, anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-NECTIN4 antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-LIV-1 antibody, anti-ROR1 antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-MUCl antibody, anti-Lewis antibody Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenas
  • the antibodies of the present invention include murine antibodies, chimeric antibodies, humanized antibodies and fully human antibodies, preferably humanized antibodies and fully human antibodies.
  • murine antibody in the present invention refers to antibodies prepared in mice according to the knowledge and skills in the art. During the preparation, a test subject is injected with a specific antigen, and then a hybridoma expressing an antibody with the desired sequence or functional characteristics is isolated.
  • chimeric antibody refers to an antibody formed by fusing the variable region of a mouse antibody with the constant region of a human antibody, which can reduce the immune response induced by the mouse antibody.
  • To establish a chimeric antibody it is necessary to first establish a hybridoma that secretes mouse-specific monoclonal antibodies, then clone the variable region genes from the mouse hybridoma cells, and then clone the constant region genes of human antibodies as needed, connect the mouse variable region genes with the human constant region genes into a chimeric gene, and then insert it into an expression vector, and finally express the chimeric antibody molecule in a eukaryotic system or a prokaryotic system.
  • humanized antibody also known as CDR-grafted antibody, refers to an antibody produced by transplanting mouse CDR sequences into the human antibody variable region framework, that is, different types of human germline antibody framework sequences. This can overcome the heterologous reaction induced by chimeric antibodies due to the large amount of mouse protein components.
  • antigen-binding fragment refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that fragments of full-length antibodies can be used to perform the antigen-binding function of an antibody.
  • binding fragments included in "antigen-binding fragments" include (i) Fab fragments, monovalent fragments consisting of VL, VH, CL and CH1 domains; (ii) F(ab')2 fragments, bivalent fragments comprising two Fab fragments connected by a disulfide bridge on the hinge region, (iii) Fd fragments consisting of VH and CH1 domains; (iv) Fv fragments consisting of the VH and VL domains of a single arm of an antibody; (v) single domain or dAb fragments (Ward et al., (1989) Nature 341: 544-546), which consist of a VH domain; and (vi) isolated complementarity determining regions (CDRs) or (vii)
  • the two domains VL and VH of the Fv fragment are encoded by separate genes, recombinant proteins can be used. Methods, by connecting them by synthetic linkers, so that they can be produced as a single protein chain in which the VL and VH regions are paired to form a monovalent molecule (called single-chain Fv (scFv); see, for example, Bird et al. (1988) Science 242: 423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci USA 85: 5879-5883).
  • single-chain Fv single-chain Fv
  • Such single-chain antibodies are also intended to be included in the term "antigen-binding fragment" of an antibody.
  • Antigen-binding portions can be produced by recombinant DNA technology or by enzymatic or chemical cleavage of intact immunoglobulins.
  • Fab is an antibody fragment having a molecular weight of about 50,000 and having antigen-binding activity, among fragments obtained by treating IgG antibody molecules with the protease papain (cleaving the amino acid residue at position 224 of the H chain), in which about half of the N-terminal side of the H chain and the entire L chain are bound together by a disulfide bond.
  • F(ab')2 is an antibody fragment having a molecular weight of about 100,000 and antigen-binding activity, obtained by digesting the portion below two disulfide bonds in the hinge region of IgG with the enzyme pepsin, and comprising two Fab regions linked at the hinge position.
  • Fab' is an antibody fragment having a molecular weight of about 50,000 and having antigen-binding activity obtained by cleaving the disulfide bond of the hinge region of the above-mentioned F(ab')2.
  • the Fab' fragment of the antibody can be produced by inserting a DNA encoding the Fab' fragment into a prokaryotic expression vector or a eukaryotic expression vector and introducing the vector into a prokaryotic organism or a eukaryotic organism to express the Fab'.
  • single-chain antibody means a molecule comprising an antibody heavy chain variable domain (or region; VH) and an antibody light chain variable domain (or region; VL) connected by a linker.
  • Such scFv molecules may have the general structure: NH2-VL-linker-VH-COOH or NH2-VH-linker-VL-COOH.
  • Suitable prior art linkers consist of repeated GGGGS amino acid sequences or variants thereof, for example using variants of 1-4 repeats (Holliger et al. (1993), Proc. Natl. Acad. Sci. USA 90: 6444-6448).
  • linkers that can be used in the present disclosure are described by Alfthan et al. (1995), Protein Eng. 8:725-731, Choi et al. (2001), Eur. J. Immunol. 31:94-106, Hu et al. (1996), Cancer Res. 56:3055-3061, Kipriyanov et al. (1999), J. Mol. Biol. 293:41-56 and Roovers et al. (2001), Cancer Immunol.
  • CDR refers to one of the six hypervariable regions within the variable domain of an antibody that primarily contribute to antigen binding.
  • One of the most commonly used definitions of the six CDRs is provided by Kabat E.A. et al. (1991) Sequences of proteins of immunological interest. NIH Publication 91-3242).
  • the Kabat definition of CDR applies only to CDR1, CDR2, and CDR3 (CDR L1, CDR L2, CDR L3 or L1, L2, L3) of the light chain variable domain, and CDR2 and CDR3 (CDR H2, CDR H3 or H2, H3) of the heavy chain variable domain.
  • vector refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been connected.
  • the vector is a "plasmid", which refers to a circular double-stranded DNA loop to which additional DNA segments can be connected.
  • the vector is a viral vector, in which additional DNA segments can be connected to the viral genome.
  • the vectors disclosed herein can replicate autonomously in the host cell into which they have been introduced (e.g., bacterial vectors and additional mammalian vectors with bacterial origins of replication) or can be integrated into the genome of the host cell after introduction into the host cell, thereby replicating with the host genome (e.g., non-additional mammalian vectors). dairy animal vector).
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 10 carbon atoms, and most preferably an alkyl group containing 1 to 6 carbon atoms.
  • C1-6 alkyl refers to a saturated straight or branched chain hydrocarbon group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5 or 6 carbon atoms).
  • C1-6 alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl, etc.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, and most preferably 3 to 8 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused and bridged cycloalkyls.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, the cycloalkyl ring contains 3 to 10 ring atoms.
  • monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
  • Polycyclic heterocyclic groups include spirocyclic, fused, and bridged heterocyclic groups.
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated ⁇ electron system, preferably 6- to 10-membered, such as phenyl and naphthyl, preferably phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is the aryl ring.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • the heteroaryl is preferably 5 to 10 members, more preferably 5 or 6 members, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, tetrazolyl, etc.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.
  • haloalkyl refers to an alkyl group substituted with one or more halo groups.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms.
  • halo refers to fluoro, chloro, bromo or iodo.
  • drug moiety refers generally to any compound having the desired biological activity and a reactive functional group for preparing the conjugates of the present invention.
  • cytotoxic compound refers to a class of drugs that can effectively kill tumor cells and inhibit their proliferation. It includes topoisomerase I (TOP1) inhibitors, microtubule polymerization inhibitors, topoisomerase II (TOP2) inhibitors, dihydrofolate reductase inhibitors, thymidine synthetase inhibitors, purine nucleoside synthetase inhibitors, ribonucleotide reductase inhibitors, DNA polymerase inhibitors, RNA polymerase II inhibitors and other compounds that can inhibit cell proliferation.
  • TOP1 topoisomerase I
  • TOP2 topoisomerase II
  • dihydrofolate reductase inhibitors dihydrofolate reductase inhibitors
  • thymidine synthetase inhibitors purine nucleoside synthetase inhibitors
  • ribonucleotide reductase inhibitors DNA polymerase inhibitors
  • RNA polymerase II inhibitors and
  • topoisomerase I (TOP1) inhibitors include but are not limited to camptothecin derivatives, such as SN-38, Dxd, Dx-8951, microtubule polymerization inhibitors, such as Eribulin, MMAE, MMAF, Maytansine, etc. (structure as follows)
  • camptothecin derivatives refers to pyrroloquinoline alkaloid derivatives, such as wait.
  • substituted and “substituted” refer to the substitution of one or more (e.g., one, two, three In some embodiments, one or four) hydrogen atoms are replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form stable compounds.
  • substituent may be (1) unsubstituted, or (2) substituted. If an atom or group is described as optionally substituted with one or more of the substituents listed, one or more hydrogens on the atom or group may be replaced with independently selected, optional substituents. If substituents are described as "independently selected from” or “each independently is”, each substituent is selected independently of the other. Thus, each substituent may be the same or different from another (other) substituent.
  • R groups such as but not limited to R2, R3, Rh, Ri, Rx and/or Ry
  • each R is selected independently, that is, it may be the same or different. The same is true for the selection of numerical values such as d, g, m, and n.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle that is administered together with the active ingredient and is suitable for contact with the tissues of humans and/or other animals within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • active ingredient refers to a chemical entity that can effectively treat one or more symptoms of a target disease or condition.
  • the term "effective amount” refers to the amount of active ingredient that, after administration, will achieve the desired effect to some extent, such as alleviating one or more symptoms of the condition being treated or preventing the occurrence of the condition or its symptoms.
  • the cell strains or cell lines used in the embodiments of the present invention can be obtained through commercial channels.
  • SK-BR-3 cell line was purchased from Nanjing Beiruiji Biotechnology Co., Ltd.;
  • NCI-N87 cell line was purchased from Nanjing Beiruiji Biotechnology Co., Ltd.;
  • T47D cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd.;
  • MDA-MB-453 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd.;
  • A375 cell line was purchased from ATCC;
  • NCI-H1703 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • compound 1-7 50 mg, 0.093 mmol was dissolved in 5 mL of ultra-dry dichloromethane, and 4-methyl-1-piperazine propionic acid (32 mg, 0.182 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80 mg, 0.449 mmol) and 4-dimethylaminopyridine (8 mg, 0.060 mmol) were added in sequence, and the reaction was allowed to proceed overnight.
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • Embodiment 5 is a diagrammatic representation of Embodiment 5:
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • Embodiment 10 is a diagrammatic representation of Embodiment 10:
  • Embodiment 11 is a diagrammatic representation of Embodiment 11:
  • compound 11-2 500 mg, 2.487 mmol was dissolved in 5 mL of toluene, (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-F]indolizine-3,6,10(4H)-one (624 mg, 2.369 mmol) and PPTS (30 mg, 0.118 mmol) were added, and the temperature was raised to 110°C for overnight reaction after nitrogen replacement three times. LC-MS monitoring showed that the raw material reacted completely.
  • Embodiment 12 is a diagrammatic representation of Embodiment 12
  • boron trichloride (26 ml, 26 mmol) was dissolved in 80 ml of dichloromethane, and 6-amino-1,4-benzodioxetine (13-1, 5 g, 33 mmol), chloroacetonitrile (3.01 g, 40 mmol) and aluminum trichloride (5.7 g, 43 mmol) were added in sequence. After stirring at 0°C for 10 minutes, the mixture was warmed to room temperature and reacted at room temperature for 10 minutes. After 10 minutes, the temperature was raised to 40°C again and kept overnight. TLC monitoring showed that the reaction was complete.
  • Embodiment 14 is a diagrammatic representation of Embodiment 14:
  • Embodiment 15 is a diagrammatic representation of Embodiment 15:
  • Embodiment 16 is a diagrammatic representation of Embodiment 16:
  • Embodiment 17 is a diagrammatic representation of Embodiment 17:
  • Embodiment 18 is a diagrammatic representation of Embodiment 18:
  • Embodiment 19 is a diagrammatic representation of Embodiment 19:
  • Embodiment 20 is a diagrammatic representation of Embodiment 20.
  • Embodiment 21 is a diagrammatic representation of Embodiment 21.
  • compound cis-3-hydroxycyclobutanecarboxylic acid (4.09 mg, 0.0353 mmol) was dissolved in 5 ml dry DCM, N-hydroxysuccinimide (4.06 mg, 0.0353 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.77 mg, 0.0353 mmol) were added to react for one hour, and then 11 (10.00 mg, 0.0235 mmol) and triethylamine (3.6 ⁇ L, 0.0259 mmol) were added to react at room temperature for 2 hours.
  • Embodiment 22 is a diagrammatic representation of Embodiment 22.
  • compound 11 (15 mg, 0.035 mmol) was dissolved in 5 ml dry DCM, compound (S)-2-hydroxypropionic acid (6.4 mg, 0.071 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (16 mg, 0.042 mmol) and N,N-diisopropylethylamine (18 ⁇ L, 0.106 mmol) were added and kept at room temperature for 2 hours.
  • Embodiment 23 is a diagrammatic representation of Embodiment 23.
  • compound 11 (15 mg, 0.035 mmol) was dissolved in 5 ml dry DCM, compound D-2-hydroxypropionic acid (6.4 mg, 0.071 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (16 mg, 0.042 mmol) and N,N-diisopropylethylamine (18 ⁇ L, 0.106 mmol) were added and kept at room temperature for 2 hours.
  • Embodiment 24 is a diagrammatic representation of Embodiment 24.
  • compound 24-1 (70 mg, 0.133 mmol) was dissolved in 10 ml dry dichloromethane, compound 6-2 (49 mg, 0.260 mmol), 4-dimethylaminopyridine (9.8 mg, 0.0798 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (122 mg, 638 mmol) were added and kept at room temperature for 1 hour.
  • Embodiment 25 is a diagrammatic representation of Embodiment 25.
  • compound 24 (5 mg, 0.0084 mmol) was dissolved in 5 ml of dry dichloromethane, and glycolic acid (1.3 mg, 0.0168 mmol), O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.8 mg, 0.0101 mmol) and N,N-diisopropylethylamine (3.3 ⁇ L, 0.0252 mmol) were added and kept at room temperature for 2 hours.
  • glycolic acid 1.3 mg, 0.0168 mmol
  • O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.8 mg, 0.0101 mmol)
  • N,N-diisopropylethylamine 3.3 ⁇ L, 0.0252 mmol
  • Embodiment 26 is a diagrammatic representation of Embodiment 26.
  • Embodiment 27 is a diagrammatic representation of Embodiment 27.
  • Embodiment 28 is a diagrammatic representation of Embodiment 28:
  • compound 11 (15 mg, 0.035 mmol) was dissolved in 5 ml dry N, N-dimethylformamide, 3-hydroxycyclopentanecarboxylic acid (9.2 mg, 0.071 mmol) and O-(7-azabenzotriazole-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (16 mg, 0.042 mmol) and N, N-diisopropylethylamine (18 ⁇ L, 0.106 mmol) were added and kept at room temperature for 2 hours.
  • Embodiment 29 is a diagrammatic representation of Embodiment 29.
  • Embodiment 30 is a diagrammatic representation of Embodiment 30.
  • Embodiment 31 is a diagrammatic representation of Embodiment 31.
  • Embodiment 32 is a diagrammatic representation of Embodiment 32.
  • Embodiment 33 is a diagrammatic representation of Embodiment 33.
  • Embodiment 34 is a diagrammatic representation of Embodiment 34.
  • Embodiment 35 is a diagrammatic representation of Embodiment 35.
  • Embodiment 36 is a diagrammatic representation of Embodiment 36.
  • compound 13 Under ice bath, compound 13 (5 mg, 0.011 mmol) was dissolved in 5 ml of dry dichloromethane, and glycolic acid (1.7 mg, 0.022 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (5 mg, 0.013 mmol) and N,N-diisopropylethylamine (5.7 ⁇ L, 0.033 mmol) were added and kept at room temperature for 2 hours.
  • glycolic acid 1.7 mg, 0.022 mmol
  • O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate 5 mg, 0.013 mmol
  • N,N-diisopropylethylamine 5.7 ⁇ L, 0.033 mmol
  • Embodiment 37 is a diagrammatic representation of Embodiment 37.
  • Embodiment 38 is a diagrammatic representation of Embodiment 38.
  • compound 13 (5 mg, 0.011 mmol) was dissolved in 5 ml dry N,N-dimethylformamide, cis-3-hydroxycyclobutanecarboxylic acid (2.6 mg, 0.022 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (4.9 mg, 0.013 mmol) and N,N-diisopropylethylamine (5.7 ⁇ L, 0.033 mmol) were added and kept at room temperature for 2 hours.
  • Embodiment 39 is a diagrammatic representation of Embodiment 39.
  • compound 39-2 (43 mg, 0.0505 mmol) was dissolved in 5 ml of dry dichloromethane, trifluoroacetic acid (2 ml) was added and the mixture was kept at room temperature for 48 hours.
  • Embodiment 40 is a diagrammatic representation of Embodiment 40.
  • Embodiment 41 is a diagrammatic representation of Embodiment 41.
  • Embodiment 42 is a diagrammatic representation of Embodiment 42.
  • compound 14 (5 mg, 0.0113 mmol) was dissolved in 5 ml dry N, N-dimethylformamide, cis-3-hydroxycyclobutanecarboxylic acid (2.6 mg, 0.0226 mmol) and O-(7-azabenzotriazole-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (5.2 mg, 0.0136 mmol) and N, N-diisopropylethylamine (5.9 ⁇ L, 0.0339 mmol) were added and kept at room temperature for 2 hours.
  • Embodiment 43 is a diagrammatic representation of Embodiment 43.
  • Embodiment 44 is a diagrammatic representation of Embodiment 44.
  • compound 15 (5 mg, 0.011 mmol) was dissolved in 5 ml dry N,N-dimethylformamide, cis-3-hydroxycyclobutanecarboxylic acid (2.6 mg, 0.022 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (4.9 mg, 0.013 mmol) and N,N-diisopropylethylamine (5.7 ⁇ L, 0.033 mmol) were added and kept at room temperature for 2 hours.
  • Embodiment 45 is a diagrammatic representation of Embodiment 45.
  • compound 15 (5 mg, 0.0116 mmol) was dissolved in 5 ml dry N, N-dimethylformamide, (S)-2-hydroxypropionic acid (1.7 ⁇ L, 0.0232 mmol) and O-(7-azabenzotriazole-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (5.3 mg, 0.0139 mmol) and N, N-diisopropylethylamine (6.1 ⁇ L, 0.0348 mmol) were added and kept at room temperature for 1 hour.
  • Embodiment 46 is a diagrammatic representation of Embodiment 46.
  • compound 46-4 (878 mg, 3.089 mmol) was dissolved in 5 mL of water and 20 mL of ethanol, and ammonium chloride (268 mg, 5.004 mmol) and iron powder (691 mg, 12.356 mmol) were added. After nitrogen replacement three times, the temperature was raised to 80 ° C and reacted overnight. LC-MS monitoring showed that the raw material was completely reacted.
  • Embodiment 47 is a diagrammatic representation of Embodiment 47.
  • Embodiment 48 is a diagrammatic representation of Embodiment 48.
  • Embodiment 49 is a diagrammatic representation of Embodiment 49.
  • Embodiment 50 is a diagrammatic representation of Embodiment 50.
  • Embodiment 51 is a diagrammatic representation of Embodiment 51.
  • Embodiment 52 is a diagrammatic representation of Embodiment 52.
  • Embodiment 53 is a diagrammatic representation of Embodiment 53.
  • Embodiment 54 is a diagrammatic representation of Embodiment 54:
  • Embodiment 55 is a diagrammatic representation of Embodiment 55:
  • Embodiment 56 is a diagrammatic representation of Embodiment 56.
  • Embodiment 57
  • Embodiment 58
  • Embodiment 59 is a diagrammatic representation of Embodiment 59.
  • Embodiment 60 is a diagrammatic representation of Embodiment 60.
  • Embodiment 62
  • Embodiment 63
  • Embodiment 64 is a diagrammatic representation of Embodiment 64.
  • Embodiment 65 is a diagrammatic representation of Embodiment 65.
  • Embodiment 66
  • Embodiment 67 is a diagrammatic representation of Embodiment 67.
  • Embodiment 68
  • Embodiment 69
  • Embodiment 70 is a diagrammatic representation of Embodiment 70.
  • Embodiment 71
  • 71-1 200 mg, 0.876 mmol and 71-2 (180 mg, 0.876 mmol) were dissolved in DMF, and TEA (0.66 mL), CuI (16.8 mg, 0.088 mmol) and PdCl 2 (PPh 3 ) 2 (61.8 mg, 0.088mmol) and then heated to 95°C under N2 protection for 6h.
  • LC-MS monitored the reaction completion, extracted with EA/ H2O , washed with saturated NaCl, dried with anhydrous Na2SO4 , filtered, dried by spin-drying, purified by normal phase column, 8% EA:PE to obtain the product, and dried by spin-drying to obtain a yellow solid (205mg, 66.4%).
  • LC-MS (ESI): m/z found [M+H] + 353.0.
  • Embodiment 72 is a diagrammatic representation of Embodiment 72.
  • compound 72-6 (12.4 mg, 0.0118 mmol) was dissolved in 5 ml of dry N,N-dimethylformamide, and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (7.8 mg, 0.0135mmol) and 1-hydroxybenzotriazole (1.9mg, 0.0135mmol) were reacted for ten minutes, and then compound 11 (5mg, 0.0118mmol) and N,N-diisopropylethylamine (3.9 ⁇ L, 0.0224mmol) were added and kept at room temperature for 2 hours.
  • Embodiment 73
  • 73-1 (410 mg, 1 mmol) was dissolved in DMF, DIEA (0.188 mL, 1.14 mmol) and HATU (0.433 g, 1.14 mmol) were added in sequence, and the mixture was reacted at room temperature for 30 min. TLC detected the formation of active ester intermediate. 73-2 (0.136 mL, 1 mmol) was added, and the mixture was reacted at room temperature for 2 h. After the reaction was complete, H 2 O/DMF was used for slurrying, suction filtration, and the filter cake was freeze-dried to obtain the product (501 mg, 95.8%).
  • LC-MS (ESI): m/z found [M+H] + 524.45.
  • Embodiment 74
  • Embodiment 75 is a diagrammatic representation of Embodiment 75.
  • Embodiment 76
  • Embodiment 77
  • Embodiment 78-80
  • Examples 78-80 were obtained.
  • Embodiment 81-82
  • Examples 81-82 were obtained.
  • Embodiment 83
  • 83-1 (100 mg, 0.326 mmol) was dissolved in THF (3 mL), and a catalytic amount of DMF was added.
  • Oxalyl chloride (138 ⁇ L, 0.038 mmol) was added dropwise at 0°C under nitrogen protection, and then reacted at room temperature for 1 h. The solution changed from turbid to clear and was concentrated under reduced pressure.
  • the acyl chloride intermediate was dissolved in DCM (2 mL), and TEA (453 ⁇ L, 3.26 mmol) and morpholine (143 ⁇ L, 1.632 mmol) were added at 0°C, and then reacted at room temperature for 2 h.
  • Embodiment 84-88
  • Embodiment 89
  • Embodiment 89
  • Embodiment 91-96
  • Examples 91-96 were synthesized by referring to the synthesis method of Example 77 and Example 88. Their structural formulas and LC-MS (ESI) are shown in Table 4.
  • Embodiment 97
  • Example 97 Except for replacing the corresponding reaction raw materials, the synthesis method of Example 97 was referred to obtain Examples 98-101, and their structural formulas and LC-MS (ESI) are shown in Table 5.
  • Embodiment 102
  • Embodiment 102
  • Embodiment 104
  • Embodiment 105-106

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

Sont divulgués dans la présente invention un nouveau dérivé de camptothécine, un lieur, un conjugué ligand-médicament et une composition pharmaceutique de celui-ci contenant le dérivé de camptothécine ou le conjugué, et l'utilisation médicale correspondante.
PCT/CN2024/091808 2023-05-08 2024-05-08 Dérivé de camptothécine, lieur, conjugué ligand-médicament et leur utilisation médicale Pending WO2024230752A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1241191A (zh) * 1996-12-20 2000-01-12 科学研究与运用咨询公司 喜树碱的新的类似物,及作为药物的用途及其药物组合物
US20100120816A1 (en) * 2006-07-26 2010-05-13 Indena S.P.A. Camptothecin derivatives with antitumor activity
CN101979392A (zh) * 2010-09-26 2011-02-23 中国人民解放军第二军医大学 7-芳乙烯基取代高喜树碱类化合物及其作为药物的用途
WO2020063676A1 (fr) * 2018-09-26 2020-04-02 江苏恒瑞医药股份有限公司 Conjugué ligand-médicament d'un analogue de l'exatécan, son procédé de préparation et application associée
WO2023030364A1 (fr) * 2021-09-01 2023-03-09 上海弼领生物技术有限公司 Composé camptothécine, son procédé de préparation et son utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1241191A (zh) * 1996-12-20 2000-01-12 科学研究与运用咨询公司 喜树碱的新的类似物,及作为药物的用途及其药物组合物
US20100120816A1 (en) * 2006-07-26 2010-05-13 Indena S.P.A. Camptothecin derivatives with antitumor activity
CN101979392A (zh) * 2010-09-26 2011-02-23 中国人民解放军第二军医大学 7-芳乙烯基取代高喜树碱类化合物及其作为药物的用途
WO2020063676A1 (fr) * 2018-09-26 2020-04-02 江苏恒瑞医药股份有限公司 Conjugué ligand-médicament d'un analogue de l'exatécan, son procédé de préparation et application associée
WO2023030364A1 (fr) * 2021-09-01 2023-03-09 上海弼领生物技术有限公司 Composé camptothécine, son procédé de préparation et son utilisation

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